As pointed out in a paper entitled "Approaches to Prevention of Epithelial Cancer During The Preneoplastic Period", Cancer Research, 36 (July, 1976), 2699-2702, presented at a Conference on "Early Lesions and The Development of Epithelial Cancer" (National Cancer Institute, Oct. 21-23, 1975), the death rates for several common forms of epithelial cancer either increased or showed no decrease during the 20-year period from 1950 to 1970. These epithelial cancer sites included the lung and pancreas in both men and women, the colon and bladder in men, the breast and ovary in women. The conventional clinical approach that has been followed with most epithelial cancer has been to wait until the patient has invasive disease and then treat this disease with cytotoxic chemotherapy, surgery, or radiation. None of these modalities has been overwhelmingly successful for the treatment of all types of epithelial cancer, in spite of some advances that have occurred.
Accordingly, it has been suggested that an alternative approach to the problem of epithelial cancer is to consider the disease as a process which takes many years to reach its final, invasive stage in man and which might be controlled by physiological or pharmacological mechanisms during its early stages, with the goal of prevention of end-stage, invasive, terminal disease.
Retinoids play an essential role in controlling the normal differentiation of epithelial tissues and are therefore important for controlling premalignant epithelial cell differentiation. It has even been found that retinoids can cause cellular repair of hyperplastic and anaplastic lesions caused by chemical carcinogens. Moreover, retinoid deficiency has been shown, in experimental animals, to enhance susceptibility to chemical carcinogenesis. Indeed, retinoids are essential for the normal cellular differentiation of epithelia that account for more than half of the total primary cancer in both men and women. These epithelia include those of the bronchi and trachea, stomach, intestine, uterus, kidney and bladder, testis, prostate, pancreatic ducts, and skin. In the absence of retinoids in the diet, normal cellular differentiation does not occur in these epithelia.
However, natural retinyl esters, such as retinyl acetate and retinyl palmitate, as well as retinoic acid, have been found to be too toxic at high dosage levels to be of practical value for cancer prevention in higher mammals. Progress has been made recently in identifying synthetic retinoids, for example 13-cis-retinoic acid, that are considerably less toxic than retinoic acid or the natural retinyl esters, and are also more potent in preventing chemical carcinogenesis. See "13-cis-Retinoic Acid:Inhibitor of Bladder Carcinogenesis in the Rat", Science, Feb. 4, 1977, Volume 195, pp 487-489 as well as "13-cis-Retinoic Acid: Inhibition of Bladder Carcinogenesis Induced in Rats by N-Butyl-N-(4-hydroxybutyl) nitrosamine", Science, Nov. 18, 1977, Volume 198, pages 743-744. 13-cis-retinoic acid, however, has not been found to be particularly effective against breast cancer in the rat model discussed hereinafter.
Recent developments in this field, as summarized above, are also discussed in an article entitled "Prevention of Chemical Carcinogenesis by Vitamin A and its Synthetic Analogs (Retinoids)", Federation Proceedings, 35, (May 1, 1976), 1332-1338, in which it is noted that it still remains a goal to find, for practical application to man and other mammals, highly effective synthetic retinoids that also have low toxicity and a high degree of tissue specificity against cancer at any particular organ site. See also the articles in the Fall, 1977, issue of The Southern Research Institute Bulletin (Volume 30, Number 2), pages 3-9 ("CHEMOPREVENTION OF CANCER--Steps Leading to Some Malignancies May Be Reversible" and "How Do Retinoids Work? Studies on Retinoic Acid-Binding Protein"). Other recent publications of interest in this field include "Biological Activity and Metabolism of the Retinoid Axerophthene (Vitamin A Hydrocarbon)", Cancer Research 38, 1734-1738, June 1978; and "Retinoids and Cancer Prevention: The importance of the Terminal Group of the Retinoid Molecule In Modifying Activity and Toxicity" in Carcinogens: Identification and Mechanism of Action, A. C. Griffin & C. R. Shaw, Editors, N.Y. Raven Press, 1978 (in Press).